Clinically amyopathic dermatomyositis manifested after the allogeneic haematopoietic stem cell transplantation: Case presentation and literature review.

Clinically amyopathic dermatomyositis (CADM) lacks muscle symptoms, associated with rapidly progressive interstitial lung disease. Anti-melanoma differentiation-associated gene 5 (MDA-5) antibody has been identified as a disease-labelling autoantibody. We report two cases of CADM manifested after the allogeneic haematopoietic stem cell transplantation (allo-HSCT)-Case 1: a 56-year-old man with acute leukaemia received the allo-HSCT and Case 2: a 45-year-old female patient with lymphoma received the allo-HSCT. She received donor lymphocyte infusion because of a post-transplant relapse. After allo-HSCT or donor lymphocyte infusion, Gottron papules emerged, and both patients were diagnosed as CADM based on dermatological findings coupled with the positivity of anti-MDA-5 antibody, accompanied by interstitial shadows consistent with ILD on chest computed tomography. Case 2 was initially diagnosed as a kind of chronic graft versus host disease. Their symptoms were improved by the combination of immunosuppressive agents with a concomitant decrease in anti-MDA-5 antibody levels. For Case 2, rituximab was subsequently started for relapse of lymphoma, resulting in a substantial decrease in the level of anti-MDA-5 antibody and improvement in rash and ILD. Our cases raise a possibility that CADM emerges after the HSCT, highlighting the importance of early diagnosis to avoid fated progression into ILD.

The Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma.

On the basis of immunohistochemistry, diffuse large B-cell lymphoma (DLBCL) is categorized as a germinal center B-cell (GCB) or non-GCB subtype. Recent integrated genomic analyses have highlighted the importance of the JAK-STAT3 pathway in the molecular pathogenesis of DLBCL. However, its relevance to clinical outcomes remains controversial. Therefore, we evaluated the extent of the nuclear expression of phosphorylated STAT3 (pSTAT3), a surrogate marker of signal transducer and activator of transcription 3 (STAT3) activation, by immunohistochemistry. We also analyzed the potential relationship between pSTAT3 positivity (defined as ≥40% positive neoplastic cells) and clinicopathologic characteristics in 294 patients with DLBCL. pSTAT3 was detected in 122 patients (42%), with a higher rate in the non-GCB subtype than in the GCB subtype (57% vs. 28%, P<0.001). Factors potentially activating STAT3, MYD88L265P, and Epstein-Barr virus-encoded small RNA were identified in the pSTAT3-positive non-GCB subtype, whereas the pSTAT3-positive GCB subtype often showed STAT3 mutations and lacked EZH2 mutations and the rearrangements of BCL2 and MYC. Multivariate analyses revealed that the pSTAT3-positive GCB subtype showed a favorable prognosis (HR: 0.17; 95% confidence interval, 0.04-0.7; P=0.014). These findings suggest that pSTAT3 positivity may have a unique impact on the clinicopathologic characteristics of DLBCL, making it a promising novel marker for the favorable prognosis of patients with the GCB subtype.

Clinicopathological features of adult T-cell leukemia/lymphoma with HTLV-1-infected Hodgkin and Reed-Sternberg-like cells.

Hodgkin and Reed-Sternberg (HRS) cells, a hallmark of classic Hodgkin lymphoma (CHL), are occasionally detected in non-Hodgkin lymphomas, including adult T-cell leukemia/lymphoma (ATLL), a lymphoid neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). HRS-like cells associated with ATLL have been described to be of B-cell lineage and infected with Epstein-Barr virus (EBV), not HTLV-1. We herein describe clinicopathological findings in 8 cases (4 males and 4 females; median age, 73 years [range, 55-81 years]) of ATLL with HTLV-1-infected HRS-like cells identified by ultrasensitive RNA in situ hybridization for HTLV-1 basic leucine zipper factor (HBZ-ISH), a specific viral transcript of HTLV-1. All patients showed nodal or mediastinal lesions, and 5 of the 8 patients were at an advanced disease stage. HRS-like cells were positive for CD30, CD15, MUM1, CD25, and HBZ-ISH and negative for B-cell markers, including PAX5, pan-T-cell antigens, and EBV in all cases. Five cases were positive for CD4, and 6 cases were positive for fascin. HBZ was identified in both HRS-like cells and surrounding lymphoid cells in 1 case with an aggressive clinical course and only HRS-like cells in 7 cases, most of whom showed a clinical response regardless of the chemotherapeutic regimen. Even though the definitive lineage typing of the HTLV-1-infected HRS cells is one of the limitations of this study in the absence of single-cell microdissection for polymerase chain reaction analysis, the combination of diffuse HBZ-ISH positivity and negativity for PAX5 and EBV deemed these cases distinct from CHL arising in HTLV-1 carriers.

Genetic profile of adult T-cell leukemia/lymphoma in Okinawa: Association with prognosis, ethnicity, and HTLV-1 strains.

Genetic alterations in adult T-cell leukemia/lymphoma (ATLL), a T-cell malignancy associated with HTLV-1, and their clinical impacts, especially from the perspective of viral strains, are not fully elucidated. We employed targeted next-generation sequencing and single nucleotide polymorphism array for 89 patients with ATLL in Okinawa, the southernmost islands in Japan, where the frequency of HTLV-1 tax subgroup-A (HTLV-1-taxA) is notably higher than that in mainland Japan, where most ATLL cases have HTLV-1-taxB, and compared the results with previously reported genomic landscapes of ATLL in mainland Japan and the USA. Okinawan patients exhibited similar mutation profiles to mainland Japanese patients, with frequent alterations in TCR/NF-ĸB (eg, PRKCB, PLCG1, and CARD11) and T-cell trafficking pathways (CCR4 and CCR7), in contrast with North American patients who exhibited a predominance of epigenome-associated gene mutations. Some mutations, especially GATA3 and RHOA, were detected more frequently in Okinawan patients than in mainland Japanese patients. Compared to HTLV-1-taxB, HTLV-1-taxA was significantly dominant in Okinawan patients with these mutations (GATA3, 34.1% vs 14.6%, P = .044; RHOA, 24.4% vs 6.3%, P = .032), suggesting the contribution of viral strains to these mutation frequencies. From a clinical viewpoint, we identified a significant negative impact of biallelic inactivation of PRDM1 (P = .027) in addition to the previously reported PRKCB mutations, indicating the importance of integrated genetic analysis. This study suggests that heterogeneous genetic abnormalities in ATLL depend on the viral strain as well as on the ethnic background. This warrants the need to develop therapeutic interventions considering regional characteristics.

Transplant-related complications are impediments to the success of allogeneic hematopoietic stem cell transplantation for adult T cell leukemia patients in non-complete remission.

Outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with adult T cell leukemia/lymphoma (ATL) are not satisfactory, particularly in patients in non-complete remission at transplantation (Pt-non-CR). We conducted a regional retrospective study in the ATL endemic area of Okinawa, Japan. Of 62 ATL patients, 21 received allo-HSCT in CR and 41 in non-CR. The 3-year overall survival (3yOS) rate and median survival time for the whole cohort was 25.6% and 7.7 months, respectively. The 3yOS of Pt-non-CR was significantly lower than that of patients in CR (Pt-CR) (16.8% vs. 43.6%, P = 0.005). Transplant-related mortality (TRM) was significantly higher in Pt-non-CR than in Pt-CR (46.3% vs. 15.7%, P = 0.025), while there was no significant difference in disease-associated mortality (DAM) between Pt-non-CR and Pt-CR. Multivariable analysis for Pt-non-CR revealed that poor performance status (poor-PS) and higher sIL-2R level (high sIL-2R) adversely affected OS. Poor-PS was associated with higher TRM, but not with higher DAM in Pt-non-CR. High sIL-2R did not affect TRM or DAM in Pt-non-CR. Overall, high TRM rates rather than DAM contribute to the poor outcomes of Pt-non-CR, suggesting that not only disease control but also management of transplant-related complications is required for allo-HSCT in ATL patients.

Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm, and is divided into 2 indolent (smoldering and chronic) and 2 aggressive (acute and lymphoma) clinical subtypes. Based on previous integrated molecular analyses suggesting the importance of the JAK-STAT pathway in ATLL, we attempted to clarify the clinicopathological significance of this pathway. Clinical and morphological findings were reviewed in 116 cases with ATLL. The nuclear localizations of phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6 were analyzed by immunohistochemistry. Targeted sequencing was undertaken on the portion of STAT3 encoding the Src homology 2 domain. Expression of pSTAT3 was observed in 43% (50/116) of ATLL cases, whereas pSTAT5 and pSTAT6 were largely undetected. Cases with the lymphoma type showed significantly less frequent pSTAT3 expression (8/45, 18%) than those with the other subtypes (41/66, 62%; P < .001). STAT3 mutations were detected in 36% (10/28) and 19% (12/64) of cases with the smoldering and aggressive types of ATLL, respectively. The correlation between STAT3 mutation and pSTAT3 expression was not significant (P = .07). Both univariate and multivariate analysis revealed that pSTAT3 expression was significantly associated with better overall survival and progression-free survival in the smoldering type of ATLL, whereas STAT3 mutation was not related to a line of clinical outcome. Collectively, our data show that only the lymphoma type showed a low prevalence of tumor cells positive for pSTAT3 expression, and raises the possibility that pSTAT3 expression is a novel biomarker to predict better prognosis in the smoldering type of ATLL.

Adipose tissue-derived mesenchymal stem cells ameliorate bone marrow aplasia related with graft-versus-host disease in experimental murine models.

Graft-versus-host disease (GVHD) constitutes the most frequent complications after the allogeneic hematopoietic stem cell transplantation for a variety of hematological malignancies. In the present study, we explored the prophylactic potential of adipose tissue-derived mesenchymal stem cells (AD-MSCs) in controlling GVHD in murine models with a special focus on bone marrow aplasia related with acute GVHD. The CB6F1 mice were induced GVHD by the injection intravenously of C57BL/6 (B6-Ly-5.1) splenocytes without conditioning irradiation or chemotherapy. AD-MSCs from C3H mice were injected intravenously via tail veins. GVHD was assessed using flowcytometry analysis of peripheral blood cells and histopathologic analysis of target organs. Histopathological analyses revealed that AD-MSCs markedly suppressed the infiltration of lymphocytes into liver as well as the aplasia in bone marrow. This study is the first to clarify the effectiveness of AD-MSCs against bone marrow aplasia in GVHD, supporting a rationale of AD-MSCs for ameliorating bone marrow suppression and infectivity after allo-HSCT in human clinics.

Evaluation of two prognostic indices for adult T-cell leukemia/lymphoma in the subtropical endemic area, Okinawa, Japan.

Aggressive adult T-cell leukemia/lymphoma (ATL) has an extremely poor prognosis and is hyperendemic in Okinawa, Japan. This study evaluated two prognostic indices (PIs) for aggressive ATL, the ATL-PI and Japan Clinical Oncology Group (JCOG)-PI, in a cohort from Okinawa. The PIs were originally developed using two different Japanese cohorts that included few patients from Okinawa. The endpoint was overall survival (OS). Multivariable Cox regression analyses in the cohort of 433 patients revealed that all seven factors for calculating each PI were statistically significant prognostic predictors. Three-year OS rates for ATL-PI were 35.9% (low-risk, n = 66), 10.4% (intermediate-risk, n = 256), and 1.6% (high-risk, n = 111), and those for JCOG-PI were 22.4% (moderate-risk, n = 176) and 5.3% (high-risk, n = 257). The JCOG-PI moderate-risk group included both the ATL-PI low- and intermediate-risk groups. ATL-PI more clearly identified the low-risk patient subgroup than JCOG-PI. To evaluate the external validity of the two PIs, we also assessed prognostic discriminability among 159 patients who loosely met the eligibility criteria of a previous clinical trial. Three-year OS rates for ATL-PI were 34.5% (low-risk, n = 42), 9.2% (intermediate-risk, n = 109), and 12.5% (high-risk, n = 8). Those for JCOG-PI were 22.4% (moderate-risk, n = 95) and 7.6% (high-risk, n = 64). The low-risk ATL-PI group had a better prognosis than the JCOG-PI moderate-risk group, suggesting that ATL-PI would be more useful than JCOG-PI for establishing and examining novel treatment strategies for ATL patients with a better prognosis. In addition, strongyloidiasis, previously suggested to be associated with ATL-related deaths in Okinawa, was not a prognostic factor in this study.

Human T-cell leukemia virus type I Tax genotype analysis in Okinawa, the southernmost and remotest islands of Japan: Different distributions compared with mainland Japan and the potential value for the prognosis of aggressive adult T-cell leukemia/lymphoma.

Okinawa, comprising remote islands off the mainland of Japan, is an endemic area of human T-cell leukemia virus type I (HTLV-1), the causative virus of adult T-cell leukemia-lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). We investigated the tax genotype of HTLV-1 among 29 HTLV-1 carriers, 74 ATL patients, and 33 HAM patients in Okinawa. The genotype distribution-60 (44%) taxA cases and 76 (56%) taxB cases-differed from that of a previous report from Kagoshima Prefecture in mainland Japan (taxA, 10%; taxB, 90%). A comparison of the clinical outcomes of 45 patients (taxA, 14; taxB, 31) with aggressive ATL revealed that the overall response and 1-year overall survival rates for taxA (50% and 35%, respectively) were lower than those for taxB (71% and 49%, respectively). In a multivariate analysis of two prognostic indices for aggressive ATL, Japan Clinical Oncology Group-Prognostic Index and Prognostic Index for acute and lymphoma ATL, with respect to age, performance status, corrected calcium, soluble interleukin-2 receptor, and tax genotype, the estimated hazard ratio of taxA compared with taxB was 2.68 (95% confidence interval, 0.87-8.25; P=0.086). Our results suggest that the tax genotype has clinical value as a prognostic factor for aggressive ATL.

Clinical usefulness of FDG-PET/CT for the evaluation of various types of adult T-cell leukemia.

PURPOSE: The aim was to explore undefined useful indices for clinically grading adult T-cell leukemia (ATL) using [18F] 2-fluoro-2-deoxyglucose (FDG) - positron emission tomography/computed tomography (PET/CT). METHODS: A total of 28 patients with ATL (indolent, 9; aggressive, 19) were enrolled; all patients with aggressive ATL underwent FDG-PET/CT before chemotherapy. Patients with indolent ATL underwent FDG-PET/CT at the time of suspected disease progression and/or transformation; some received lymph node biopsy. The quantitative parameters maximum standardized uptake values (SUVmax), and mean and peak SUV, metabolic tumor volume (MTV), and volume-based total lesion glycolysis were calculated with the margin threshold as 25%, and 50% of the SUVmax for all lesions. RESULTS: All parameters except for MTV-25% showed significant differences (P ≤ 0.05) in differentiating the aggressive type from the indolent type of ATL. Areas under the curve for receiver-operating characteristic (ROC) analysis regarding the series of parameters investigated ranged from 0.75 to 0.92; this indicated relatively high accuracy in distinguishing the aggressive type from the indolent type. No malignant findings were detected in lymph node biopsies in indolent ATL patients with lymphadenopathy. DISCUSSION: We performed evaluation of a line of parameters of FDG-PET, thereby demonstrating their significantly high accuracy for grading malignancy in ATL patients. In particular, low accumulation of FDG in indolent ATL patients with lymphadenopathy might predict that it is not a sign of disease transformation, but rather a reactive manifestation. CONCLUSION: FDG-PET/CT findings could be useful for clinically grading ATL.

An atypical case of late-onset systemic lupus erythematosus with systemic lymphadenopathy and severe autoimmune thrombocytopenia/neutropenia mimicking malignant lymphoma.

Here, we report a rare case of systemic lupus erythematosus (SLE) with conspicuous manifestation of hematological abnormalities. At onset, the 52-year-old male patient showed systemic lymphadenopathy and splenomegaly, severe autoimmune thrombocytopenia, and autoimmune neutropenia. Bone marrow examination and lymph node biopsy excluded the possibility of malignant lymphoma. Based on laboratory findings, he was finally diagnosed with combined autoimmune cytopenia coupled with SLE. Atypical clinical manifestations of SLE prompted us to explore the possibility of autoimmune lymphoproliferative syndrome (ALPS). However, we did not detect an increased number of CD4-/CD8-, CD3+, TCRαß+ double-negative T cells in the circulating blood or dysfunctional T cell apoptosis in the Fas/Fas ligand pathway due to mutations in the FAS, FASLG or CASP10 genes. Combined autoimmune cytopenia is a rare clinical entity that in some cases co-occurs with other autoimmune diseases. Given that most SLE patients presenting atypical hematological manifestations at an early stage subsequently exhibit typical systemic manifestations, the present case raises the possibility that initial hematological abnormalities may be signs of unexpected SLE manifestations.

Characterization of patients with aggressive adult T-cell leukemia-lymphoma in Okinawa, Japan: a retrospective analysis of a large cohort.

Okinawa Prefecture, located in the subtropics, is an area of endemic adult T-cell leukemia-lymphoma (ATL) in Japan. We retrospectively analyzed 659 patients with aggressive ATL in seven institutions in Okinawa between 2002 and 2011. The median patient age was 68 years. More patients were aged ≥90 years (2.6 %), in this study, than in a nationwide survey (<1 %). The median survival time (MST) of the entire cohort was 6.5 months. Of the 217 patients who had a clinical status similar to that stated in the eligibility criteria of JCOG9801 (a randomized phase III study comparing VCAP-AMP-VECP with CHOP-14), 147 who received the CHOP regimen had a poorer MST than those in the CHOP-14 arm of JCOG9801 (8 vs 11 months). The prevalence of strongyloidiasis in the ATL patients was much higher (12.4 %) than in the historical cohort who visited the University of the Ryukyus Hospital (3.4 %). Furthermore, strongyloidiasis may be associated with ATL-related deaths. These findings suggest that, compared with other areas in Japan, in Okinawa, the proportion of patients aged ≥90 years with clinical features of aggressive ATL is higher, outcomes are poorer, and the disease is associated with a higher prevalence of strongyloidiasis.

Recurrence of Psoriasis Vulgaris Accompanied by Treatment with C-C Chemokine Receptor Type 4 (CCR4) Antibody (Mogamulizumab) Therapies in a Patient with Adult T cell Leukemia/ Lymphoma: Insight into Autoinflammatory Diseases.

Adult T cell leukemia / lymphoma (ATL) is one of the most aggressive hematological malignancies caused by human T-lymphotropic virus type-I (HTLV-1). Mogamulizumab is a new defucosylated humanized monoclonal antibody agent which targets C-C chemokine receptor type 4 (CCR4) expressed occasionally on the surface of ATL cells. However, adverse events such as drug eruptions have also been highlighted, at least in part, via the dysfunction of regulatory T cells (Tregs). We herein report a pronounced recurrence of systemic psoriasis vulgaris accompanied by the treatment of mogamulizumab in a patient with ATL. Pathological examinations may suggest a mechanistic link between the recurrence of autoinflammatory diseases and anti-CCR4 antibody therapies.

Giant Septic Lymphadenitis with Marked Gas Formation Caused by Bacteroides fragilis in a Patient with Adult T-cell Leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) sometimes causes opportunistic infections. A 53-year-old woman with systemic lymphadenopathies was diagnosed with ATL by inguinal lymph node biopsies and underwent oral chemotherapy. Two months later, high grade fever, lower abdominal pain and lymphadenopathy recurred. Computed tomography revealed the presence of lymphadenopathy with marked gas formation in the pelvic lesion. Blood cultures were suggestive of septic lymphadenitis by Bacteroides fragilis (BF). This represents the first demonstration of giant lymphadenitis with gas formation caused by BF in a patient with ATL. Notably, septic lymphadenitis is pivotal in the differential diagnosis of systemic lymphadenopathy in ATL.

Fatal pneumonia and viremia due to human parainfluenza virus type 1 in a patient with adult T-cell leukemia-lymphoma treated with mogamulizumab.

We report a case of fatal pneumonia and viremia due to human parainfluenza virus type 1 (HPIV-1) in a 65-year-old male patient with adult T-cell leukemia-lymphoma (ATL) treated with mogamulizumab, a brand-new therapeutic agent for ATL. To our knowledge, this is the first report describing viremia due to HPIV-1. After administering mogamulizumab, lymphocyte count in the blood was drastically decreased and the patient suffered from complicated infections including gram-negative bacterial sepsis, cytomegalovirus antigenemia and aspergillosis. Although these infections were successfully controlled by broad spectrum antimicrobial therapy, patchy ground-grass opacities in the both lungs were gradually worsened. He finally died due to acute respiratory failure. Since findings of the chest CT was consistent with typical patterns of viral pneumonia, we screened major respiratory viruses in the peripheral blood with multiplex PCR, and it turned out that RNA of HPIV-1 was positive. Although ATL cells were not detected in the autopsied lungs and a variety of other tissues, cytoplasmic inclusion bodies, which are commonly observed in RNA viral infection, were abundantly observed in the autopsied lung tissue. These findings suggest that mogamulizumab accomplished complete remission of ATL, while the chemotherapy-induced prolonged lymphopenia caused fatal pneumonia and viremia due to HPIV-1. As it has been well recognized that community respiratory viruses including HPIV-1 often cause fatal pneumonia in patients with leukemia, but also there is no specific treatment for HPIV-1, we have to enforce standard precautions especially when we treat leukemic patients with intensively immunosuppressive agents such as mogamulizumab.

The intractable intra-abdominal hemorrhage with unknown etiology in a patient with severe hemophilia A.

Severe hemophilia patients are more likely to be complicated by intra-articular hemorrhage, subcutaneous hemorrhage, and intra-mascular hemorrhage. Spontaneous intra-abdominal hemorrhage is a rare fatal disease, which is an arterial bleeding of uncertain causes from vessel feeding arteries. In case the spontaneous intra-abdominal hemorrhage is complicated to severe hemophilia patients, the mortality rate increases considerably. We experienced a patient with severe hemophilia A, who made a full recovery from spontaneous intra-abdominal hemorrhagic shock by replacement therapy of coagulation factor VII, a noninvasive procedure.

A rare case of septic pulmonary embolism caused by infection-associated catheter removal in a patient with Hodgkin's lymphoma.

As a reflection of the considerable increase in the number of cancer patients treated with chemotherapy, indications for the use of implanted venous catheters are rapidly growing. However, in some cases, implanted venous catheters induce unwelcome complications. We herein report a rare case of septic pulmonary embolism (SPE) caused by local infection-associated catheter removal during the administration of ABVd combination chemotherapy consisting of adriamycin, bleomycin, vinblastine and dacarbazine in a patient with Hodgkin's lymphoma of the mixed cellularity type. During the course of treatment with chemotherapy administered via implanted venous catheters, think it is crucial to monitor for the potential occurrence of SPE.